Methods of solubilizing coumermycin employing urea, dimethylacetamide or mixtures thereof

ABSTRACT

A therapeutic composition is described which comprises a mixture of (1) coumermycin and (2) (a) dimethylacetamide, (b) urea or (c) a mixture of dimethylacetamide and urea. The composition can be formulated into suitable dosage forms for oral administration and, when so administered, satisfactory blood levels are achieved at relatively low dosages.

United States Patent 1 3,627,886

[ 72] Inventor Harold Leon Newman-k OTHER REFERENCES Chem. Abstracts,Vol. 58, pg. 6656c (1963) [21] Appl. No. 721,154

Primary Examiner-Stanley J. Friedman Assistant Examiner-Vincent D.Turner AnorneysSamuel L. Welt, Jon S. Saxe, William H. Epstein,

Gerald S. Rosen, Bernard S. Leon and William G. lsgro [22] Filed Apr.15, 1968 [45] Patented Dec. 14, 1971 [73] Assignee HoHmann-La Roche Inc.

Nutley, NJ.

ABSTRACT: A therapeutic composition is described which comprises amixture of (l) coumermycin and (2) (a) dimethylacetamide, (b) urea or(c) a mixture of [54] METHODS OF SOLUBILIZING COUMERMYCIN EMPLOYINGUREA, DIMETHYLACETAMIDE OR MIXTURES THEREOF I I 2 Claims, No Drawlnssdimethylacetamrde and urea. I

The composmon can be formulated into suitable dosage [52] U.S.Cl 424/181forms f ("3| administration and when so administered Int-cl satisfactoryblood levels are achieved at relatively low [50] Field of Search260/2l0; dosages [56] References Cited UNITED STATES PATENTS 3,20l,3868/1965 Kawaguchietal 260/210 METHODS OF SOLUBILIZING COUMERMYCINEMPLOYING UREA, DIMETI-IYLACETAMIDE OR MIXTURES THEREOF BRIEF SUMMARY OFTHE INVENTION The present invention provides compositions which containthe known antibiotic coumermycin in admixture with either (a)dimethylacetamide or (b) urea or (c) with a mixture of dimethylacetamideand urea. The compositions are produced simply by mixing coumermycinwith dimethylacetamide, urea 10 BACKGROUND OF THE INVENTION Theantibiotic coumermycin is produced by culturing Streptomyces hazeliensisvar. hazeliensis nov. sp., an organism isolated from a sample of soilobtained in Matane, Gaspe, Canada. A culture of the organism has beendeposited in the collection of micro-organisms in the U.S. Department ofI Agriculture, Northern Utilization Research and Development Division,Peoria, lll. under Reg. No. NRRL 2938.

Processes for producing the antibiotic, described, for example, inBelgium Pat. No. 665,237, Dec. 10, 1965, result in a crude complex ofantibiotic compounds. At least five active components and an inactivefraction can be isolated from this complex. Of the active components,the compound denoted coumermycin A is the most active. Coumermycin A isfully methylpyrollated and it has the following formula:

The utility of coumermycin has, in the past, been limited by its poorand inconsistent absorption into the blood stream from thegastrointestinal tract when administered orally. Accordingly, in orderto offset the undesirably absorption characteristics of the drug, it hasbeen necessary to administer coumermycin in high oral dosages in orderto achieve therapeutically effective blood levels. This solution to theproblem, however, leaves much to be desired since inherent in theadministration of high dosages of coumermycin is the risk of severetoxic reactions, e.g., gastrointestinal disturbances.

DETAILED DESCRIPTION The present invention provides new and usefulcompositions which contain coumermycin as the active ingredient.

More particularly, the invention provides coumermycincontainingcompositions which are suitable for oral administration.

In its most specific embodiment, the invention providescoumennycin-containing pharmaceutical compositions, in unit dosage form,which compositions are especially characterized in that, whenadministered orally even at relatively low dosages, high blood levelsare achieved.

The compositions of the invention are mixtures comprising (1)coumermycin and (2) (a) dimethylacetamide or (b) urea or (c) a mixtureof dimethylacetamide and urea. The compositions may contain also, asoptional components, other materials, of the type described hereinafter,which, in some instances at least, appear to complement the blood levelenhancing properties of dimethylacetamide and/or urea. Additionally, thecompositions may contain conventional pharmaceutical excipients andadjuvants.

In carrying out the invention, any therapeutically active component ofthe coumermycin complex can be used. Such component can be in the formof the free acid or in the form of a salt of the free acid. Thus,suitable for use are salts of coumermycin, such as, alkali metal salts,for example, sodium, potassium and lithium. Additionally, amine salts ofcoumermycin free acid, for example, the diethanolamine salt or thetriethanolamine salt of coumermycin can be used. In the preferredembodiment of the invention, coumermycin A,, either the free acid or analkali metal salt thereof, for example, the monosodium salt, isemployed. It is to be understood that the previously mentioned salts ofcoumermycin are merely illustrative of the salts which can be employedin the practice of the invention and such listing is not intended aslimitative on the practice of the invention. In general, one can use asalt of coumermycin free acid with any medicinally acceptable base. Inthe paragraphs which follow, the term coumermycin will be used todenote, collectively and individually, the active components of thecoumermycin complex both in the form of the free acid and in the form ofsalts thereof with a medicinally acceptable base.

The compositions ofv the invention are readily produced. The preparativemethod involves simply mixing or dissolving coumermycin withdimethylacetamide, urea or with a mixture of dimethylacetamide and urea.Generally, the mixing step is carried out without the aid of a solvent.However, if desired, the ingredients can be admixed in a liquid vehiclewhich is a solvent for both. In those instances in which urea is used asthe blood level enhancing agent, the urea may be melted by heating toapproximately 132 C., and the coumermycin dissolved in the melt. Coolingand grinding the solid mass gives fine particles with good absorptionproperties. The quantity of coumermycin and the quantity ofdimethylacetamide and/or urea which is used in producing thecompositions is variable within certain prescribed limits. In general,the compositions of the invention will contain from about 0.l part byweight to about 50 parts by weight of dimethylacetamide, urea or mixtureof dimethylacetamide and urea for each part by weight of coumermycinpresent. The compositions which are produced in the preferred embodimentof the invention, however, will contain from about 1 part by weight toabout 10 parts by weight of dimethylacetamide, urea or mixture ofdimethylacetamide and urea for each part by weight of coumermycinpresent.

The compositions of this invention, i.e., the mixture of coumermycinwith dimethylacetamide or with urea or with the mixture ofdimethylacetamide and urea, are ultimately worked-up to providepharmaceutical preparations which are suitable for oral administration.These pharmaceutical preparations may be in solid form, for example,tablets, dragees or capsules. The tablets can be single or multilayerand/or they may be coated. In the alternative, the preparations may bein liquid form, for example, solutions, emulsions or suspensions. Inproducing these pharmaceutical preparatiogs,

conventional pharmaceutically acceptable adjuvants and excipients,either organic or inorganic in nature, are employed. Such adjuvants andexcipients include water, gelatin, lactose, starches, magnesiumstearate, talc, vegetable oils, gums, petroleum jellies, glycerol, ethylalcohol, propylene glycol and other such materials. The methods andtechniques as well as the adjuvants and excipients which are used informulating the compositions of the present invention into particularsolid oral dosage forms will be readily apparent to those skilled in theart. For example, the compositions, with or without appropriatepharmaceutical excipients and adjuvants, can be filled into hard or softshell capsules. In the alternative, the compositions can be compressedinto tablets which can, if desired, be film-coated or sugar-coated. Themanner in which the present compositions are formulated into liquidpharmaceutical preparations, e.g., solutions for oral administration,will similarly be apparent to persons skilled in the art. For example,in producing solutions, the mixture of coumermycin withdimethylacetamide or with urea or with a dimethylacetamide-urea mixturecan be dissolved in a pharmaceutically acceptable solvent. in analternate embodiment of the invention, coumermycin and dimethylacetamideor urea or the dimethylacetamide-urea mixture can be added separately tothe pharmaceutical excipients or adjuvants, either liquid or solid toform, in situ, the desired mixture of medicament and blood levelenhancing agent or agents.

In addition to the essential components enumerated heretofore, thecompositions of the invention can contain other ingredients, some ofwhich appear to complement the ability of dimethylacetamide and/or ureato achieve high blood levels of coumermycin. Such ingredients include,for example, organic carboxylic acid and salts of organic carboxylicacids. Among the acids which can be used, as optical components in thepractice of the invention, are aliphatic monocarboxylic acids having acarbon chain length of two to 20 carbon atoms, such as, acetic acid,propionic acid, oleic acid, stearic acid, lauric acid, etc. Salts ofgluconic acid, for example, sodium gluconate can also be employed.Additionally, vegetable oils, such as, corn oil, safflower oil, as wellas mono-,di-, and triesters of glycerol, for example, glycerylmonooleate, glyceryl monostearate, glyceryl dioleate, glyceryltriacetate, etc., can be used in admixture with dimethylacetamide and/orurea. Furthermore, the invention contemplates the use of polyoxyethylenesorbitan esters, for example, polyoxyethylene 20 sorbitan monooleatewhich is commercially available under the trade name Tween 80,polyoxyethylene 20 sorbitan monostearate which is commercially availableunder the trade name Tween 60 and certain polyoxyethylene ethers, forexample, polyoxyethylene ether of caster oil which is commerciallyavailable under the trade name Emulphor EL 620, in combination withdimethylacetamide and/or urea. Additionally, polyethylene glycols;products produced by condensing ethylene oxide with a propyleneglycol-propylene oxide condensate; and N-methyl glucamine, can be usedin admixture with dimethylacetamide and/or urea. The amount of optionalingredients used in the practice of the invention is variable withincertain prescribed limits. Generally, however, it is preferred that thequantity of such optional ingredients present in the compositions doesnot exceed the weight of dimethylacetamide and/or urea used.

The quantity of inert pharmaceutical excipients and adjuvants used inproducing various dosage forms will vary depending upon the propertiesand characteristics of the excipients or adjuvants in use and the natureof the dosage form to be formulated. in general, however, pharmaceuticalpreparations of the present invention, in unit dosage form, will providefrom about mg. of coumermycin to about 400 mg. of coumermycin. Thefrequency with which the phannaceutical preparations of this inventionare administered will vary depending upon the level of active medicamentpresent therein and the needs and requirements of the subject to betreated. in general, however, in the case of capsules or tabletscontaining 50 mg. of coumennycin, a typical adult dose is one tablet orcapsule four times daily or every 6 hours. In the case of a capsule ortablet containing l00 mg. of coumermycin, a typical adult dose of suchcapsule or tablet would be one capsule every 12 hours or twice daily. Itshould be understood, however, that the dosages enumerated herein areexemplary only and that they are not intended to limit the scope orpractice of the present invention. in any particular instance, thedosage can be adjusted to satisfy the needs and requirements of thesubject to be treated.

The present invention serves to provide pharmaceutical compositions, inunit dosage form, which contain coumermycin as the active ingredient.The compositions, thus produced, are suitable for use in the oraltreatment of microbial infections. When so used, high blood levels willbe achieved even at relatively low dosages. The invention, therefore, isof significant importance since it provides means whereby coumermycincan be self-administered by the subject, with the assurance that theactive ingredient will be absorbed reliably and consistently into thebloodstream. In the past, administration of coumermycin in the absenceof medically trained personnel, was not feasible due to the relativelyhigh dosages of coumermycin required to achieve therapeuticallyeffective blood levels, reliably and consistently.

For a fuller understanding of the nature and objects of this invention,reference may be had to the following examples which are given merely asfurther illustrations of the invention and are not to be construed in alimiting sense.

EXAMPLE I In this example, parts by weight of the monosodium salt ofcoumermycin were dissolved in 400 parts by weight of dimethylacetamide.The solution, thus obtained, was filled into hard shell gelatin capsulesto provide capsules, each of which contained 100 mg. of the monosodiumsalt of coumermycin and 400 mg. of dimethylacetamide.

The solution, produced as described in the preceding paragraph wasadministered orally to dogs and blood level determinations were made atspecific intervals. The blood assays were performed by microbiologicalcup-plate assay method using Staphylococcus aureus as the test organism.The blood level detenninations were made 1, 2, 4, -7 and 24 hours afteroraladministration of the capsules. For control purposes, capsulescontaining 50 mg. of the monosodium salt of coumermycin and nodimethylacetamide were also administered orally to a dog and blood leveldeterminations were made at 2 and 4 hours after oral administration.

The table which follows hereinafter, sets forth the results of the bloodlevel determinations.

' Blood level, mcg./ml., hours after administration Dose, mgJkg. 1 2 4 724 Product of- Example 1 50 0. 1 0.3 30 3 1 Control 5 0.4 0.6

The foregoing results demonstrate that the oral administration ofcoumermycin in the form of a solution in dimethylacetamide enhances theabsorption of the active medicament into the blood stream.

EXAMPLE 2 a. In this example, a composition was produced by mixing 50parts by weight of the monosodium salt of coumermycin with 300 parts byweight of urea. The dry mixture was filled into hard shell gelatincapsules to provide capsules, each of which contained 50 mg. of themonosodium salt of coumermycin and 300 mg. of urea.

b. A second composition was produced using 50 parts by weight of themonosodium salt of coumermycin and 250 parts by weight of urea. in thisinstance, the mixture of monosodium salt of coumermycin and urea washeated to a temperature above its melting point, following which themolten mass was cooled to room temperature. The solid product, which wasobtained on cooling, was comminuted to provide small particles. Theproduct was filled into hard shell gelatin capsules to provide capsules,each of which contained 50 mg. of the monosodium salt of coumermycin and250 mg. of urea.

c. A third was produced by heating to a temperature above its meltingpoint, a mixture of parts by weight of the monosodium salt ofcoumermycin and 50 parts by weight of urea. The mixture was allowed tocool to room temperature, following which the solid product, thusobtained, was comminuted to relatively fine particles. These particleswere filled into hard shell gelatin capsules to provide capsules, eachof which contained 10 mg. OF the monosodium salt of coumermycin and 50mg. of urea.

d. The compositions, produced as described in paragraphs (a) to (c),inclusive, of this example, were administered orally to dogs and bloodlevel determinations were made at specific intervals. The blood assayswere performed by microbiological cup-plate assay method usingStaphylococcus aureus as the test organism. The blood leveldeterminations were made l, 2, 4, 7 and 24 hours after oraladministration of the capsules. For control purposes, capsulescontaining 50 mg. of the monosodium salt of coumermycin and no urea werealso administered orally to dogs and blood level determinations weremade at 2 and 4 hours after oral administration.

The table which follows hereinafter, sets forth the results of the bloodlevel determinations.

Blood level, meg/ml hours after administration Dose, mgJkg. 1 2 4 7 24Product of- Example 2(a) 5 2 5 0.08 Example 2(b).. 5 Example 2(c).... 1l. 5 1. Control 5 0. 4 0. 6

TE foregoing results demonstrate that the oral administration ofcoumennycin in combination with urea enhances the absorptions of theactive medicament into the blood stream.

EXAMPLE 3 level determinations.

Blood level, mcg./ml., hours after administration Dose, mg./kg. 1 2 4 724 Product oi- Example 3... 50 10 3 3 1 0. 1 Control 5 0.4 0.6

"m. V, V M

EXAMPLE 4 in this example, the products were prepared by mixing thehereinafter indicated ingredients, in the quantities designated, andfilling and mixtures thus obtained into hard shell gelatin capsules.

Quantity mg./capsules Ingredients 1 2 3 4 5 Monosodium salt ofcoumermycin 100 100 100 50 10 Dimethylacetamlde 250 250 250 200 200Tween 80; Emulphor EL-6 Pluronic F438. .Urea 2 0 The products, thusobtained, were administered orally to dogs and blood leveldeterminations were made as described in example i. For controlpurposes, capsules containing 50 mg. of the monosodium salt ofcoumermycin and no blood level enhancing agent were administered orallyto dogs and blood level determinations were made 2 to 4 hours after oraladministration. The results of such determinations are set forth in thetable which follows:

hereinafter indicated ingredients, in the quantities designated, andsubsequently filling such mixtures into hard shell gelatin capsules.

Quantity, mg./capsule Ingredients 1 2 3 Monosodium salt of coumermycin.50 50 50 Dimethylacetarnide 200 200 200 'lrlacetin 300 Medium chaintriglyceride 300 Corn oil 300 Water :IIIIIII:::::::.

l Medium Chain Triglycerides-a selected liquid fraction made fromcoconut oil. Available from Drew Chemical Company.

The foregoing mixtures were administered orally to dogs and blood leveldeterminations were carried out as described in example 1.-For controlpurposes, capsules containing 50 mg. of the monosodium salt ofcoumermycin and no blood level enhancing agent were also administered todogs and blood levels were determined. The results of suchdeterminations are set forth in the table which follows:

Blood levels, mcg./ml., hours after administration Dos e, 1 mgjk g. l 24 7 24 Pr u t. N- 5 0.15 6 1 30 5 0. 3 Control 5 0. 4

EXAMPLE 6 In this example, an elixir-type solution was prepared bycharging the following named ingredients into a suitable vessel toprovide a product containing, per ml. of solution, 25 mg. of themonosodium salt of coumermycin, 9 percent by weight ofdimethylacetamide, 35 percent by weight of polyethylene glycol, 35percent by weight of ethyl alcohol and 10 percent by weight of water.The solution was administered orally to dogs in a dosage of 50 mg./kg.of body weight and blood levels were determined l, 2, 4, 7 and 24 hoursafter oral administration. The results of the blood level determinationswere as follows:

1 hour 0.3 mcgJml. 2 hours L3 meg/ml. 4 hours 2.5 meg/ml. 7 hours 0.04mcgJmI. 24 hours 0.04 rncg./ml.

EXAMPLE 7 In this example, 50 parts by weight of the monosodium salt ofcoumermycin was mixed with 15 parts by weight of anhydrous aluminumchloride to form an aluminum salt complex of coumermycin. Thereafter,the complex was added to 400 parts. by weight of dimethylacetamide whichcontained 25 parts by weight of sodium gluconate. The product, thusobtained, was filled into hard shell capsules, to provide capsules eachof which contained the equivalent of 50 mg. of the monosodium salt ofcoumerrnycin.

The product produced as described in the preceding paragraph, wasadministered orally to dogs and blood level determinations were carriedout as described in example 1. For control purposes, capsules containing50 mg. of the monosodium salt of coumermycin and no dimethylacetamide orsodium gluconate were also administered orally to dogs and blood levelswere subsequently determined. The results of the blood leveldeterminations are set forth in the table which follows:

Blood levels, megJmL, hours after administration Dose, mg./kg. 1 2 4 724 Product oi Example? 50 0.3 1.3 2.5 004 0.04 Control 6 0.4 0.6

EXAMPLE 8 In this example, a product was prepared by mixing 50 parts 7by weight of the monosodium salt of coumermycin, 100 parts mycin and nourea or N-metliylglucamine were also administered orally to dogs andblood levels were determined.

The results of such determinations are set forth in the table 1. Amethod for increasing the absorption of orally administered coumermycininto the blood stream from the gastrointestinal tract which comprisesthe oral administration of an effective amount of a compositionsconsisting of an active ingredient selected from the group consistingof:

a. the product of admixing from about 0.1 part to about 50.0 parts byweight dimethylacetamide and one part by weight of a coumennycin freeacid or a salt thereof with a medicinally acceptable base;

b. the product of heating in admixture from about 0.l part to about 50.0parts by weight of urea and one part by weight of a coumermycin freeacid or a salt thereof with a medicinally acceptable base to atemperature sufficient to melt said urea, cooling said mixture to form asolid and comminuting said solid; and

c. the product of admixing from about 0.1 parts by weight to about 50.0parts by weight of a mixture of dimethylacetamide and urea and one partby weight of a coumermycin free acid or a salt thereof with amedicinally acceptable base; and a pharmaceuticall acceptable carriertherefor. 2. The method of claim 1 w erein the coumermycin free acid insaid active ingredient is coumermycin A free acid.

l i l

2. The method of claim 1 wherein the coumermycin free acid in saidactive ingredient is coumermycin A1free acid.